1. © G.K.Raju, Ph.D. Manufacturing Science May 21st 2003 MANUFACTURING SCIENCE: The Means To GMPs In the 21 st Century.. G.K.Raju, Ph.D.

2. © G.K.Raju, Ph.D. Manufacturing Science OUTLINE l “MANUFACTURING SCIENCE”: A DEFINITION l “MANUFACTURING SCIENCE”: DIMENSIONS l MANUFACTURING SYSTEM: “HERE” l MANUFACTURING SYSTEM: TO “THERE” l IMPLICATIONS

3. © G.K.Raju, Ph.D. Manufacturing Science “MANUFACTURING” l “Manufacturing” (derived from Latin) = “manus” (hand) + “factus” (made) = “made by hand” l “Manufacturing” is the transformation of materials and information into goods for the satisfaction of human needs Material Information

4. © G.K.Raju, Ph.D. Manufacturing Science “SCIENCE” l A body of knowledge, body of facts or information, body of laws or principles, body of truths, or verities or realities…… l Skill, expertise, mastery, know-how l Organized knowledge l A means of solving problems.. The Synonym Finder J. I. Rodale

5. © G.K.Raju, Ph.D. Manufacturing Science “MANUFACTURING SCIENCE” “Manufacturing”“Science” “ Manufacturing Science” A body of knowledge, body of facts or information, body of laws or principles, body of truths, or verities or realities…… Transformation of materials and information into goods for the satisfaction of human needs

6. © G.K.Raju, Ph.D. Manufacturing Science “MANUFACTURING SCIENCE”: A DEFINITION Body of Knowledge, Laws, Principles Involved In The Transformation of Materials and Information into Goods for the Satisfaction of Human Needs

7. © G.K.Raju, Ph.D. Manufacturing Science OUTLINE l “MANUFACTURING SCIENCE”: A DEFINITION l “MANUFACTURING SCIENCE”: DIMENSIONS l MANUFACTURING SYSTEM: “HERE” l MANUFACTURING SYSTEM: TO “THERE” l IMPLICATIONS

8. © G.K.Raju, Ph.D. Manufacturing Science “MANUFACTURING SCIENCE”: DIMENSIONS Body of Knowledge, Laws, Principles Involved In The Transformation of Materials and Information into Goods for the Satisfaction of Human Needs Extent Of Mfg. Science

9. © G.K.Raju, Ph.D. Manufacturing Science “MANUFACTURING SCIENCE” : Levels of Knowledge Extent Of Mfg. Science PROCESS KNOWLEDGE How, Correlative.. CAUSAL KNOWLEDGE Why? MECHANISTIC KNOWLEDGE First Principles DESCRIPTIVE KNOWLEDGE: What, Etc, …

10. © G.K.Raju, Ph.D. Manufacturing Science “MANUFACTURING SCIENCE”: DIMENSIONS Body of Knowledge, Laws, Principles Involved In The Transformation of Materials and Information into Goods for the Satisfaction of Human Needs Extent Of Mfg. Science

11. © G.K.Raju, Ph.D. Manufacturing Science “MANUFACTURING SCIENCE”: The “Time” Dimension THE DESIRED STATE Extent Of Mfg. Science Time “Right First Time” LEVEL 1 LEVEL 2 LEVEL 4 LEVEL 5 LEVEL 3 FDA Minimum Requirement Manufacturing Centric Approach to Manufacturing Science (“learning by doing”) Design/Development Centric Approach Manufacturing Science (“learning before doing”)

12. © G.K.Raju, Ph.D. Manufacturing Science “MANUFACTURING SCIENCE”: DESIRED RELATIVE TO CURRENT STATE (Personal Opinion) Extent Of Mfg. Science Time “Right First Time” LEVEL1 LEVEL2 LEVEL 4 LEVEL5 LEVEL3 FDA Minimum Requirement Manufacturing Centric Approach to Manufacturing Science (“learning by doing”) Design/Development Centric Approach Manufacturing Science (“learning before doing”)

13. © G.K.Raju, Ph.D. Manufacturing Science OUTLINE l “MANUFACTURING SCIENCE”: A DEFINITION l “MANUFACTURING SCIENCE”: DIMENSIONS l MANUFACTURING SYSTEM: “HERE” l MANUFACTURING SYSTEM: TO “THERE” l IMPLICATIONS

14. © G.K.Raju, Ph.D. Manufacturing Science “MANUFACTURING SYSTEM” A “manufacturing system” is set of processes and systems (and people) bound by a common material and information flow. Material Information WEIGH WET GRANULN STEPFB DRY STEP BLEND ENCAPSULATE SIEVE QC 1 QC 3 QC 4 DRY MIX QC 2

15. © G.K.Raju, Ph.D. Manufacturing Science ACTIVE FORMULNFILL PACK ACTIVE FORMULNFILLPACK ACTIVE FORMULNFILLPACK RESEARCH DEVELOPMENT MANUFACTURING TIME SPACE PHARMACEUTICAL MANUFACTURING SYSTEM COST QUALITY TIME SAFETY

16. © G.K.Raju, Ph.D. Manufacturing Science PROCESS A WITH QC TESTS WEIGHING WET GRANULATION STEPFB DRY STEP BLEND ENCAPSULATESIEVE API MICRO Particle Size Description ID Assay CU Impurity Dissolution MICRO QC 1 QC 3 QC 4 DRY MIX QC 2 LOD

17. © G.K.Raju, Ph.D. Manufacturing Science OUTLINE l “MANUFACTURING SCIENCE”: A DEFINITION l “MANUFACTURING SCIENCE”: DIMENSIONS l MANUFACTURING SYSTEM: “HERE” l MANUFACTURING SYSTEM: TO “THERE” l IMPLICATIONS

18. © G.K.Raju, Ph.D. Manufacturing Science “MANUFACTURING SCIENCE” : Levels and Focus Extent Of Mfg. Science PROCESS KNOWLEDGE How, Correlative.. CAUSAL KNOWLEDGE Why? MECHANISTIC KNOWLEDGE First Principles DESCRIPTIVE KNOWLEDGE: What, Etc, …

19. © G.K.Raju, Ph.D. Manufacturing Science “MANUFACTURING SCIENCE”: DESIRED RELATIVE TO CURRENT STATE (Personal Opinion) Extent Of Mfg. Science Time “Right First Time” LEVEL1 LEVEL2 LEVEL 4 LEVEL5 LEVEL3 FDA Minimum Requirement Manufacturing Centric Approach to Manufacturing Science (“learning by doing”) Design/Development Centric Approach Manufacturing Science (“learning before doing”)

20. © G.K.Raju, Ph.D. Manufacturing Science OUTLINE l “MANUFACTURING SCIENCE”: A DEFINITION l “MANUFACTURING SCIENCE”: DIMENSIONS l MANUFACTURING SYSTEM: “HERE” l MANUFACTURING SYSTEM: TO “THERE” l IMPLICATIONS

21. © G.K.Raju, Ph.D. Manufacturing Science Food & Drug Administration: August 21 st 2002 The FDA Announced today that the Agency will be undertaking a Significant new initiative concerning the regulation of pharmaceutical Manufacturing and product quality. The initiative, Pharmaceutical cGMPs for the 21 st Century: A Risk Based Approach… -- Lester Crawford FDA Deputy Commissioner Pharmaceutical cGMPs Initiative

22. © G.K.Raju, Ph.D. Manufacturing Science US FDA cGMPs FOR THE 21 st CENTURY  Science Based  Risk Based  Modern Quality Management Techniques  Harmonization

23. © G.K.Raju, Ph.D. Manufacturing Science U.S. FDA cGMPs FOR THE 21 st CENTURY  Science Based  Risk Based  Modern Quality Management Techniques  Harmonization

24. © G.K.Raju, Ph.D. Manufacturing Science PROCESS A WITH QC TESTS WEIGHING WET GRANULATION STEPFB DRY STEP BLEND ENCAPSULATESIEVE API MICRO Particle Size Description ID Assay CU Impurity Dissolution MICRO QC 1 QC 3 QC 4 DRY MIX QC 2 LOD

25. © G.K.Raju, Ph.D. Manufacturing Science FDA PAT Initiative The FDA Process Analytical Technologies (PAT) Initiative Is An Effort To Facilitate The Introduction of New Technologies To The Manufacturing Sector Of The Pharmaceutical Industry

26. © G.K.Raju, Ph.D. Manufacturing Science CYCLE TIME COMPONENTS

27. © G.K.Raju, Ph.D. Manufacturing Science ON-LINE TECHNOLOGY IMPACTS DOMINANT CYCLE TIMES On-line LIF, NIR, Pattern Recognition, etc.

28. © G.K.Raju, Ph.D. Manufacturing Science ACTIVE FORMULNFILL PACK ACTIVE FORMULNFILLPACK ACTIVE FORMULNFILLPACK RESEARCH DEVELOPMENT MANUFACTURING TIME SPACE Which Products? High Volume Complex Liquid Blending Drying Granulation Flow Tableting Transport Assay Fermentation Rapid Microbial Detection 10% 5% 1% 0.5% 0.1% PHARMACEUTICAL MANUFACTURING: The PAT Opportunity..

29. © G.K.Raju, Ph.D. Manufacturing Science U.S. FDA cGMPs FOR THE 21 st CENTURY  Science Based  Risk Based  Modern Quality Management Techniques  Harmonization

30. © G.K.Raju, Ph.D. Manufacturing Science “MANUFACTURING SCIENCE” : IMPLICATIONS Extent Of Mfg. Science PROCESS KNOWLEDGE How, Correlative.. CAUSAL KNOWLEDGE Why? MECHANISTIC KNOWLEDGE First Principles DESCRIPTIVE KNOWLEDGE: What, Etc, … FDA

31. © G.K.Raju, Ph.D. Manufacturing Science U.S. FDA cGMPs FOR THE 21 st CENTURY  Science Based  Risk Based  Modern Quality Management Techniques  Harmonization

32. © G.K.Raju, Ph.D. Manufacturing Science “MANUFACTURING SCIENCE” : Levels of Knowledge Extent Of Mfg. Science PROCESS KNOWLEDGE How, Correlative.. CAUSAL KNOWLEDGE Why? MECHANISTIC KNOWLEDGE First Principles DESCRIPTIVE KNOWLEDGE: What, Etc, …

33. © G.K.Raju, Ph.D. Manufacturing Science US FDA cGMPs FOR THE 21 st CENTURY  Science Based  Risk Based  Modern Quality Management Techniques  Harmonization

34. © G.K.Raju, Ph.D. Manufacturing Science APPROACH TO LEARNING: Current ApproachProposed Approach x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x xx x x xxx x x x x x x x x x x x x x x x x x x x x x x x x x xx x x xxx x x x x x x x x Process Development Commercial Production 1a 1b 2a 2b Consequences on Process Development & Commercial Production

35. © G.K.Raju, Ph.D. Manufacturing Science “MANUFACTURING SCIENCE”: DESIRED RELATIVE TO CURRENT STATE (Personal Opinion) Extent Of Mfg. Science Time “Right First Time” LEVEL1 LEVEL2 LEVEL 4 LEVEL5 LEVEL3 FDA Minimum Requirement Manufacturing Centric Approach to Manufacturing Science (“learning by doing”) Design/Development Centric Approach Manufacturing Science (“learning before doing”)

36. © G.K.Raju, Ph.D. Manufacturing Science US FDA cGMPs FOR THE 21 st CENTURY  Science Based  Risk Based  Modern Quality Management Techniques  Harmonization

37. © G.K.Raju, Ph.D. Manufacturing Science Pharmaceutical Manufacturing Research Development Manufacturing Marketing ????

38. © G.K.Raju, Ph.D. Manufacturing Science “MANUFACTURING SCIENCE” : Levels of Knowledge Extent Of Mfg. Science PROCESS KNOWLEDGE How, Correlative.. CAUSAL KNOWLEDGE Why? MECHANISTIC KNOWLEDGE First Principles DESCRIPTIVE KNOWLEDGE: What, Etc, …

39. © G.K.Raju, Ph.D. Manufacturing Science “MANUFACTURING SCIENCE” : IMPLICATIONS Extent Of Mfg. Science PROCESS KNOWLEDGE How, Correlative.. CAUSAL KNOWLEDGE Why? MECHANISTIC KNOWLEDGE First Principles DESCRIPTIVE KNOWLEDGE: What, Etc, … FDA

40. © G.K.Raju, Ph.D. Manufacturing Science OUTLINE l “MANUFACTURING SCIENCE”: A DEFINITION l “MANUFACTURING SCIENCE”: DIMENSIONS l MANUFACTURING SYSTEM: “HERE” l MANUFACTURING SYSTEM: TO “THERE” l IMPLICATIONS

41. © G.K.Raju, Ph.D. Manufacturing Science May 21 st 2003 PHARMA MANUFACTURING SCIENCE: The Means To GMPs In the 21 st Century G.K.Raju, Ph.D.